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zoom RSS 抗ガン剤が腫瘍の発育を助長する

<<   作成日時 : 2009/03/26 01:08   >>

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 あまりに低濃度で投与すると、腫瘍発育を阻害するはずの薬剤がガンに燃料供給することがわかった。
 腫瘍血管の成長を妨げる抗血管新生薬と呼ばれる薬剤についての研究である。
 同系の薬剤として、AvastinとSutentがあるが、この研究には含まれていない。
 Cilengitideについての研究。脳腫瘍を持つ少しの患者が多量投与により利益を得たけれどもそれが、最も多くの患者には効果がなかったと気付いた。
 腎癌にSutent、大腸癌にAvastinが使用されるが、作用機序は同じで、目標が異なる。数ヶ月の延命効果がある。この研究により、さらに効果的な使用法がわかる可能性がある。なぜ効果がない場合があるのかといった機序の解明に役立つかもしれない。
 国立研究所は先月、Avastinを進行した大腸癌に推薦することをやめることにした。
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Page last updated at 00:56 GMT, Monday, 23 March 2009
Cancer drug 'fuels tumour growth'
http://news.bbc.co.uk/2/hi/health/7954472.stm

画像Tumour blood vessels (in red), surrounded by cancer cells (in blue)

A type of drug designed to stunt tumour growth has actually been found to fuel cancer if given at too low a dose.

UK scientists were investigating a kind of drug called an anti-angiogenesis, still under development, which hampers the growth of tumour blood vessels.

Avastin and Sutent, which act in a similar way, have been proven to work and were not covered in this research.

But cancer experts say the study in Nature Medicine could help make those drugs more effective.

The researchers focused on a drug called Cilengitide which is designed to prevent blood vessel cells sticking together and moving - an important part of angiogenesis.

Previous tests on people have found that a few patients with brain tumours benefited from high doses of the drug, but that it failed to work for most.


Knowledge of this mechanism will help us develop new ways to make these drugs as effective as possible
Dr Andy Reynolds, Institute of Cancer Research
In this research, tests carried out on mice showed that low doses of Cilengitide actually stimulated the growth of cancers.

Further investigation showed it did this by switching on a molecule called VEGFR2, which triggers the angiogenesis process.

That is significant because although when a patient is initially given a drug, its level in the blood rises quickly ensuring a big dose goes to the tumour, after a while levels start to fall as the body begins to deal with the drug.

This is likely to be why trials of the drug have shown such poor results.

Caveat

Dr Kairbaan Hodivala-Dilke of the Institute of Cancer, who led the study, said it was important that the trials looking at this drug continued.

"We've got evidence now that low doses can enhance tumour growth. So there is no benefit of giving a high dose, which then drops, and then a high dose again.

"But that's not to say it can't work at all. It can, but there is this caveat."

She said it may be more effective to give the drug via an infusion pump, which would allow the dosage to remain topped up at an effective level.


Sutent and Avastin have proven effective enough for use in the NHS but there is still need to understand why they can sometime fail
Dr Lesley Walker, Cancer Research UK

Dr Andy Reynolds, from the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research, who also worked on the study, said: "Knowledge of this mechanism will help us develop new ways to make these drugs as effective as possible.

"In the future, we may be able to combine these inhibitors with other drugs to maximise their effectiveness for patients."

Dr Lesley Walker, director of cancer information at Cancer Research UK, which helped fund the research, said: "This study is important because it may help to explain the mixed results previously seen in patients and turn around disappointing results so people may still benefit from the drug without the potential harm."

Mechanisms

The research also has implications for the existing drugs Sutent, used to treat kidney cancer, and Avastin, for colorectal cancer.

They work by the same process, but on different targets.

At the moment, they can extend a patient's life by several months. Experts hope that this research could lead to a better understanding of the drugs' mechanisms and so to ways of making them more effective.

Dr Walker said: "Sutent and Avastin have proven effective enough for use in the NHS but there is still need to understand why they can sometime fail.

"It may be that there are similar mechanisms at work."

Last month, the National Institute for Health and Clinical Excellence - the NHS's drugs appraisal body - said Sutent could be considered for people with advanced kidney cancer. However, it decided against recommending Avastin for advanced colorectal cancer.

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Nature Medicine (22 March 2009) | doi:10.1038/nm.1941;

Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors

Andrew R Reynolds , Ian R Hart , Alan R Watson , Jonathan C Welti , Rita G Silva , Stephen D Robinson , Georges Da Violante , Morgane Gourlaouen , Mishal Salih , Matt C Jones , Dylan T Jones , Garry Saunders , Vassiliki Kostourou , Fran|[ccedil]|oise Perron-Sierra , Jim C Norman , Gordon C Tucker & Kairbaan M Hodivala-Dilke
Abstract

Inhibitors of αvβ3 and αvβ5 integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic αvβ3 and αvβ5 inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering αvβ3 integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.

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